Quinazoline derivatives

ABSTRACT

Compounds of the formula: ##STR1## are described wherein R 1 , R 2 , R 3  and A are described in the claims. These compounds show significant dopamine receptor agonist activity.

The present invention relates to novel quinazoline derivatives andpharmaceutically acceptable salts thereof.

More particularly, it relates to novel quinazoline derivatives andpharmaceutically acceptable salts thereof, which display effects on theperipheral or central nervous system, to processes for the preparationthereof, to a pharmaceutical composition comprising the same, to a useof the same as a medicament and to a method of the therapeutic treatmentof diseases in a human being or animal.

Accordingly, one object of the present invention is to provide novelquinazoline derivatives and pharmaceutically acceptable salts thereof,which display effects on the peripheral or central nervous system, inparticular on the peripheral nervous system.

Another object of the present invention is to provide processes for thepreparation of novel quinazoline derivatives and salts thereof.

A further object of the present invention is to provide a pharmaceuticalcomposition comprising, as an active ingredient, said quinazolinederivatives and pharmaceutically acceptable salts thereof.

Still further object of the present invention is to provide a use ofsaid quinazoline derivatives and pharmaceutically acceptable saltsthereof as a dopamine receptor agonist,5-HT receptor antagonist,especially 5-HT₂ receptor antagonist; α₁ receptor antagonist; and thelike and a method of the therapeutic treatment of dopamine receptor;5-HT receptor, especially 5-HT receptor; α₁ -receptor mediated diseases,particularly hypertension, cardiovascular disorder (e.g. anginapectoris, myocardial infarction, etc.), Parkinsonism, and the like, in ahuman being or animal.

The object quinazoline derivatives are novel and can be represented bythe following general formula: ##STR2## in which R¹ and R² are eachhydrogen, halogen, nitro, amino, protected amino, hydroxyamino, loweralkyl, hydroxy, protected hydroxy, sulfamoyl, carboxy, protectedcarboxy, mercapto, heterocyclic-carbonyl, heterocyclic-(lower)alkyl,lower alkylthio, hydroxy(lower)alkyl or protected hydroxy(lower)alkyl,

R³ is aryl which may have suitable substituent(s), and

A is lower alkylene, and pharmaceutically acceptable salts thereof.

Suitable salts of the object compound (I) are pharmaceuticallyacceptable, conventional non-toxic salts and may include a salt with abase such as an inorganic base salt, for example, an alkali metal salt(e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt(e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organicbase salt, for example, an organic amine salt (e.g. triethylamine salt,pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); a saltwith an acid such as inorganic acid addition salt (e.g. hydrochloride,hydrobromide, sulfate, phosphate, etc.), an organic acid addition salt(e.g. formate, acetate, trifluoroacetate, maleate, tartrate, fumarate,methanesulfonate, benzenesulfonate, etc.); a salt with a basic or acidicamino acid (e.g. arginine, aspartic acid, glutamic acid, etc.); and thelike.

According to the present invention, the object compound (I) orpharmaceutically acceptable salts thereof can be prepared by theprocesses as illustrated by the following reaction schemes. ##STR3##wherein R¹, R², R³ and A are each as defined above,

one of R_(a) ¹ and R_(a) ² is nitro while the other is hydrogen,halogen, nitro, amino, protected amino,hydroxyamino, lower alkyl,hydroxy, protected hydroxy, sulfamoyl, carboxy, protected carboxy,mercapto, heterocyclic-carbonyl, heterocyclic-(lower)alkyl, loweralkylthio, hydroxy(lower)alkyl or protected hydroxy(lower)alkyl,

one of R_(b) ¹ and R_(b) ² is hydroxyamino or amino while the other ishydrogen, halogen, nitro, amino, protected amino, hydroxyamino, loweralkyl, hydroxy, protected hydroxy, sulfamoyl, carboxy, protectedcarboxy, mercapto, heterocyclic-carbonyl, heterocyclic-(lower)alkyl,lower alkylthio, hydroxy(lower)alkyl or protected hydroxy(lower)alkyl,

one of R_(c) ¹ and R_(c) ² is amino while the other is hydrogen,halogen, nitro, amino, protected amino, hydroxyamino, lower alkyl,hydroxy, protected hydroxy, sulfamoyl, carboxy, protected carboxy,mercapto, heterocyclic-carbonyl, heterocyclic-(lower)alkyl, loweralkylthio, hydroxy(lower)alkyl or protected hydroxy(lower)alkyl,

one of R_(d) ¹ and R_(d) ² is protected amino while the other ishydrogen, halogen, nitro, amino, protected amino, hydroxyamino, loweralkyl, hydroxy, protected hydroxy, sulfamoyl, carboxy, protectedcarboxy, mercapto, heterocyclic-carbonyl, heterocyclic-(lower)alkyl,lower alkylthio, hydroxy(lower)alkyl or protected hydroxy(lower)alkyl,

one of R_(e) ¹ and R_(e) ² is protected hydroxy or protectedhydroxy(lower)alkyl while the other is hydrogen, halogen, nitro, amino,protected amino, hydroxyamino, lower alkyl, hydroxy, protected hydroxy,sulfamoyl, carboxy, protected carboxy, mercapto, heterocyclic-carbonyl,heterocyclic-(lower)alkyl, lower alkylthio, hydroxy(lower)alkyl orprotected hydroxy(lower)alkyl,

one of R_(f) ¹ and R_(f) ² is hydroxy or hydroxy(lower)alkyl while theother is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino,lower alkyl, hydroxy, protected hydroxy, sulfamoyl, carboxy, protectedcarboxy, mercapto, heterocyclic-carbonyl, heterocyclic-(lower)alkyl,lower alkylthio, hydroxy(lower)alkyl or protected hydroxy(lower)alkyl,

one of R_(g) ¹ and R_(g) ² is protected carboxy while the other ishydrogen, halogen, nitro, amino, protected amino, hydroxyamino, loweralkyl, hydroxy, protected hydroxy, sulfamoyl, carboxy, protectedcarboxy, mercapto, heterocyclic-carbonyl, heterocyclic-(lower)alkyl,lower alkylthio, hydroxy(lower)alkyl or protected hydroxy(lower)alkyl,

one of R_(h) ¹ and R_(h) ² is carboxy while the other is hydrogen,halogen, nitro, amino, protected amino, hydroxyamino, lower alkyl,hydroxy, protected hydroxy, sulfamoyl, carboxy, protected carboxy,mercapto, heterocyclic-carbonyl, heterocyclic-(lower)alkyl, loweralkylthio, hydroxy(lower)alkyl or protected hydroxy(lower)alkyl,

R⁴ is esterified carboxy, and

X is a leaving group.

The compounds (II) and (IV) used in the Processes 1 and 4 are new andcan be prepared, for example, by the following methods or a conventionalmanner. ##STR4## in which R¹, R², R³, R⁴ and A are each as definedabove.

Some of the starting materials of the above Method A are new and can beprepared, for example, according to the method of Preparation asmentioned below, or in a conventional manner.

In the above and subsequent descriptions of the present specification,suitable examples and illustrations of the various definitions which thepresent invention includes within the scope thereof are explained indetail as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s), preferably 1to 4 carbon atom(s), unless otherwise indicated.

Suitable "lower alkyl" may include straight or branched one such asmethyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and thelike.

Suitable "lower alkoxy" may include straight or branched one such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy,hexyloxy, and the like, in which the most preferable one may be methoxy.

Suitable "aryl which may have suitable substituent(s)" may includephenyl, tolyl, xylyl, cumenyl, mesithyl, naphthyl, and the like, each ofwhich may be substituted by one or more, preferably one or twosubstituent(s) such as halogen (e.g. fluorine, chlorine, bromine,iodine), lower alkyl as mentioned above (e.g. methyl, etc.), and thelike, in which more preferred example may be phenyl which is substitutedor unsubstituted by a group consisting of halogen and lower alkyl, andthe most preferred one may be phenyl, 4-chloro(or fluoro)phenyl and4-tolyl.

Suitable "protected carboxy" may include carbamoyl, esterified carboxywherein "esterified carboxy" can be referred to the ones as mentionedbelow, and the like.

Suitable examples of the ester moiety of an esterified carboxy may bethe ones such as lower alkyl ester (e.g. methyl ester, ethyl ester,propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butylester, pentyl ester, hexyl ester, etc.) which may have at least onesuitable substituent(s), for example, lower alkanoyloxy(lower)alkylester (e.g. acetoxymethyl ester, propionyloxymethyl ester,butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester,hexanoyloxymethyl ester, 1-(or 2-)acetoxyethyl ester, 1-(or 2- or3-)acetoxypropyl ester, 1-(or 2- or 3- or 4-)acetoxybutyl ester, 1-(or2-)propionyloxyethyl ester, 1-(or 2- or 3-)propionyloxypropyl ester,1-(or 2-)butyryloxyethyl ester, 1-(or 2-)isobutyryloxyethyl ester, 1-(or2-)pyvaloyloxyethyl ester, 1-(or 2-)hexanoyloxyethyl ester,isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester,3,3-dimethylbutyryloxymethyl ester, 1-(or 2-)pentanoyloxyethyl ester,etc.], lower alkanesulfonyl(lower)alkyl ester (e.g. 2-mesylethyl ester,etc.), mono(or di or tri)halo(lower)alkyl ester (e.g. 2-iodoethyl ester,2,2,2-trichloroethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkylester (e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethylester, propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester,1-(or 2-)methoxycarbonyloxyethyl ester, 1-(or 2-)ethoxycarbonyloxyethylester, 1-(or 2-) isopropoxycarbonyloxyethyl ester, etc.],phthalidylidene(lower)alkyl ester, or (5-loweralkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester (e.g.(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; lower alkenyl ester(e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynylester, propynyl ester, etc.); ar(lower)alkyl ester [e.g. mono- or di- ortriphenyl(lower)alkyl ester, etc.] which may have at least one suitablesubstituent(s) (e.g. lower alkoxy, nitro, hydroxy, lower alkyl, etc.),for example, mono- or di- or triphenyl(lower)alkyl ester which may have(lower)alkoxy [e.g. benzyl ester, benzhydryl ester, trityl ester,phenethyl ester, 4-methoxybenzyl ester, 3,4-dimethoxybenzyl ester,bis(methoxyphenyl)methyl ester, etc.], nitrophenyl(lower)alkyl ester(e.g. 4-nitrobenzyl ester, etc.),[hydroxy]-(lower)alkylphenyl(lower)alkyl ester (e.g.4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); aryl ester which may haveat least one suitable substituent(s) (e.g. phenyl ester, 4-chlorophenylester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester,cumenyl ester, etc.); phthalidyl ester; and the like.

More preferable example of the protected carboxy thus defined may becarbamoyl and lower alkoxycarbonyl.

Suitable "protected amino" may include amino protected by a conventionalamino-protective group as mentioned below.

Suitable "amino-protective group" may include acyl such as aliphaticacyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substitutedwith aromatic or heterocyclic group(s) derived from carboxylic,carbonic, sulfonic and carbamic acids.

The aliphatic acyl may include saturated or unsaturated, acyclic orcyclic ones, for example, alkanoyl such as lower alkanoyl (e.g. formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,hexanoyl, etc.), alkylsulfonyl such as lower alkylsulfonyl (e.g. mesyl,ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), carbamoyl,N-alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.),alkoxycarbonyl such as lower alkoxycarbonyl (e.g. methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl,etc.), alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g.vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as loweralkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.),cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g.cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.),and the like.

The aliphatic acyl substituted with aromatic group(s) may includearalkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g.benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like.

These acyl groups may be further substituted with one or more suitablesubstituent(s) such as nitro, halogen as mentioned below, and the like,and preferable acyl having such substituent(s) may benitroaralkoxycarbonyl (e.g. nitrobenzyloxycarbonyl, etc.),trihalo(lower)alkyl (e.g. trifluoroacetyl, etc.), and the like.

Preferable example of amino-protective group thus defined may be:

lower alkanoyl (e.g. acetyl, etc.);

trihalo(lower)alkanoyl such as trifluoro(lower)alkanoyl (e.g.trifluoroacetyl, etc.);

lower alkoxycarbonyl (e.g. ethoxycarbonyl, etc.);

carbamoyl;

N-(lower)alkylcarbamoyl (e.g. N-ethylcarbamoyl, etc.);

lower alkylsulfonyl (e.g. mesyl, ethylsulfonyl, etc.); and the like.

"Protected hydroxy" means a hydroxy group protected by a conventionalhydroxy-protective group, and suitable "hydroxy-protective group mayinclude lower alkyl as defined above, acyl as defined above,ar(lower)alkyl such as mono-, di- or triphenyl(lower)alkyl (e.g. trityl,etc.), preferably lower alkyl and triphenyl(lower)alkyl, and the mostpreferably methyl and trityl.

Suitable heterocyclic group in "heterocyclic-carbonyl" and"heterocyclic-(lower)alkyl" may include 3 to 10, preferably 5 or6-membered heteromonocyclic group containing at least one hetero atomsuch as oxygen atom, nitrogen atom and sulfur atom (e.g. morpholino,etc.), and the like.

Suitable lower alkyl group in "heterocyclic-(lower)alkyl" can bereferred to the ones as mentioned above.

Suitable "halogen" may be fluorine, chlorine, bromine, iodine, and morepreferred example may be chlorine.

Suitable "lower alkylene" may include straight or branched one such asmethylene, ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, methylmethylene, ethylethylene, propylene, and the like,in which the most preferred one may be tetramethylene.

Suitable "leaving group" may include imidazole, lower alkylimidazole(e.g. 2-methylimidazole, etc.), an acid residue such as halogen asmentioned above (e.g. chlorine, etc.), and the like.

Suitable "lower alkylthio" may include straight or branched one such asmethylthio, ethylthio, propylthio, isopropylthio, butylthio,t-butylthio, pentylthio, hexylthio, and the like.

Suitable "esterified carboxy" means the same ones as mentioned in theexplanation of protected carboxy, in which more preferable example maybe lower alkoxycarbonyl and the most preferable one may beethoxycarbonyl.

Suitable "hydroxy(lower)alkyl" may include hydroxymethyl, hydroxyethyl,hydroxypropyl, hydroxyhexyl, and the like.

Suitable "protected hydroxy(lower)alkyl" means hydroxy(lower)alkylprotected by a conventional hydroxy-protective group as mentioned in theexplanation of "protected hydroxy", in which more preferable example maybe lower alkoxy(lower)alkyl and triphenyl(lower)alkoxy(lower)alkyl, andthe most preferable one may be methoxymethyl and trityloxymethyl.

The processes for the preparation of the object compound (I) of thepresent invention are explained in detail in the following.

(1) Process 1

The compound (I) or salts thereof can be prepared by reacting thecompound (II) or salts thereof with the compound (III).

Suitable salts of the compound (II) may be acid addition salts such asthose given for the compound (I).

Suitable example of the compound (III) may includeN,N'-carbonyldiimidazole, N,N'-carbonylbis(2-methylimidazole), phosgeneor its reactive equivalent (e.g. dimer or trimer thereof, etc.), and thelike.

This reaction can be carried out in a conventional solvent which doesnot adversely influence the reaction such as dichloromethane, pyridine,N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, etc., or amixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under from warming to heating.

(2) Process 2

The compound (I-b) or salts thereof can be prepared by subjecting thecompound (I-a) or salts thereof to reduction of nitro group(s) of R_(a)¹ and/or R_(a) ².

Suitable salts of the compounds (I-a) and (I-b) may be the same as thosefor the compound (I).

The present reaction is usually carried out by a conventional method asmentioned below.

REDUCTION METHOD

The reduction method applicable for this reaction may includeconventional ones which are capable of converting a nitro group to ahydroxyamino group, for example, reduction using tin(II) chloride orzinc powder; reduction using a combination of a metal (e.g. zinc, zincamalgam, etc.) or a salt of chrome compound (e.g. chromous chloride,chromous acetate, etc.) and an organic or inorganic acid (e.g. aceticacid, propionic acid, hydrochloric acid, sulfuric acid, etc.);conventional catalytic reduction in the presence of a conventionalmetallic catalyst such as palladium catalysts (e.g. spongy palladium,palladium black, palladium oxide, palladium on carbon, colloidalpalladium, palladium on barium sulfate, palladium on barium carbonate,palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reducednickel, nickel oxide, Raney nickel, etc.), platinum catalysts (e.g.platinum plate, spongy platinum, platinum black, colloidal platinum,platinum oxide, platinum wire, etc.); reduction using aluminum amalgam;electrolytic reduction; and the like.

In case that the catalytic reduction is applied, the reaction ispreferably carried out around neutral condition.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, alcohol (e.g.methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, aceticacid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), andthe like, or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under from warming to heating.

(3) PROCESS 3

The compound (I-d) or salts thereof can be prepared by introducing anamino-protective group(s) into the compound (I-c) or salts thereof.

Suitable salts of the compounds (I-c) and (I-d) may be the same as thosefor the compound (I).

Suitable introducing agent of the amino-protective group used in thisreaction may be a conventional one which is capable of introducing theamino-protective group such as acyl as mentioned before, for example,lower alkyl isocyanate (e.g. ethyl isocyanate, etc.); alkali metalcyanate (e.g. potassium cyanate, etc.); lower alkyl halo(lower)alkanate(e.g. ethyl chloroformate, etc.); carboxylic acid, carbonic acid,sulfonic acid and their reactive derivative (e.g. an acid halide, anacid anhydride, an activated amide, an activated ester, etc.); and thelike. Preferable example of such reactive derivative may include loweralkanoic acid halide (e.g. acetyl chloride, etc.); lower alkanesulfonylhalide (e.g. mesyl chloride, ethanesulfonyl chloride, etc.); a mixedacid anhydride with an acid such as substituted phosphoric acid (e.g.dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.),dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuricacid sulfonic acid (e.g. methanesulfonic acid, toluenesulfonic acid,etc.), mono(lower)alkyl ester of carbonic acid, aliphatic carboxylicacid (e.g. pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylicacid (e.g. benzoic acid, etc.); a symmetrical acid anhydride such aslower alkanoic anhydride (e.g. acetic anhydride, etc.),trihalo(lower)alkanoic anhydride (e.g. trifluoroacetic anhydride, etc.);an activated acid amide with a heterocyclic compound containing iminofunction such as imidazole, 4-substituted imidazole, dimethylpyrazole,triazole and tetrazole; an activated ester (e.g. p-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesylphenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,pyridyl ester, piperidinyl ester, 8-quinolyl thioester, or an ester witha N-hydroxy compound such as N,N-dimethylhydroxylamine,1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide,1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, etc.); and thelike.

This reaction can be carried out in the presence of a base or an acidaccording to the introducing agent of the amino-protective group to beused.

Suitable base may include an organic or inorganic base such as alkalimetal (e.g. lithium, sodium, potassium, etc.), alkaline earth metal(e.g. calcium, etc.), alkali metal hydride (e.g. sodium hydride, etc.),alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metalhydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkalimetal carbonate (e.g. sodium carbonate, potassium carbonate, etc.),alkali metal bicarbonate (e.g. sodium bicarbonate, potassiumbicarbonate, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodiumethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid(e.g. sodium acetate, etc.), trialkylamine (e.g. triethylamine, etc.),pyridine compound (e.g. pyridine, lutidine, picoline,4-dimethylaminopyridine, etc.), quinoline, and the like.

Suitable acid may include an organic acid (e.g. formic acid, aceticacid, propionic acid, trifluoroacetic acid, benzenesulfonic acid,p-toluenesulfonic acid, etc.) and an inorganic acid (e.g. hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.).

In case that the introducing agent of the amino-protective group is usedin a free form or its salt in this reaction, the reaction is preferablycarried out in the presence of a condensing agent such as a carbodiimidecompound [e.g. N,N'-dicyclohexylcarbodiimide,N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide,N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide,N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc.], a keteniminecompound (e.g. N,N'-carbonylbis(2methylimidazole),pentamethyleneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimine, etc.); an olefinic or acetylenic ethercompounds (e.g. ethoxyacetylene, β-chlorovinylethyl ether), a sulfonicacid ester of N-hydroxybenzotriazole derivative [e.g.1-(4-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, etc.], acombination of trialkylphosphite or triphenylphosphine and carbontetrachloride, disulfide or diazenedicarboxylate (e.g. diethyldiazenedicarboxylate, etc.), a phosphorus compound (e.g. ethylpolyphosphate, isopropyl polyphosphate, phosphoryl chloride, phosphorustrichloride, etc.), thionyl chloride, oxalyl chloride,N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3-sulfonate, areagent (referred to a so-called "Vilsmeier reagent") formed by thereaction of an amide compound such as N,N-di(lower)alkylformamide (e.g.dimethylformamide, etc.), N-methylformamide or the like with a halogencompound such as thionyl chloride, phosphoryl chloride, phosgene or thelike.

The reaction is usually carried out in a conventional solvent which doesnot adversely influence the reaction such as water, acetone,dichloromethane, alcohol (e.g. methanol, ethanol, etc.),tetrahydrofuran, pyridine, N,N-dimethylformamide, etc., or a mixturethereof, and further in case that the amino-introducing agent is inliquid, it can also be used as a solvent.

The reaction temperature is not critical and the reaction is usuallycarried out under from cooling to heating.

(4) PROCESS 4

The compound (I) or salts thereof can be prepared by reacting thecompound (IV) or salts thereof with a base.

Suitable salts of the compound (IV) may be the same as those for thecompound (I).

Suitable base used in this reaction may be the same as those given inthe explanation of Process 3.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as tetrahydrofuran,dioxane, water, methanol, ethanol, etc., or a mixture thereof.

The reaction temperature is not critical, and the reaction is usuallycarried out under from warming to heating.

(5) PROCESS 5

The compound (I-f) or salts thereof can be prepared by subjecting thecompound (I-e) or salts thereof to a removal reacting of the hydroxyprotective group(s) in R_(e) ¹ and/or R_(e) ².

Suitable salts of the compounds (I-e) and (I-f) may be the same as thosefor the compound (I).

The present reaction is usually carried out by a conventional methodsuch as hydrolysis, reduction, and the like.

(i) HYDROLYSIS

The hydrolysis is preferably carried out in the presence of a base or anacid. Suitable base may include an alkalimetal hydroxide (e.g. sodiumhydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide(e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metalhydride (e.g. sodium hydride, potassium hydride, etc.), alkaline earthmetal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g.sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), analkali metal carbonate (e.g. sodium carbonate, potassium carbonate,etc.), and alkaline earth metal carbonate (e.g. magnesium carbonate,calcium carbonate, etc.), an alkali metal bicarbonate (e.g. sodiumbicarbonate, potassium bicarbonate, etc.), and the like.

Suitable acid may include an organic acid (e.g. formic acid, aceticacid, propionic acid, trifluoroacetic acid, benzenesulfonic acid,p-toluenesulfonic acid, etc.) and an inorganic acid (e.g. hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.). Theacidic hydrolysis using trifluoroacetic acid is usually accelerated byaddition of cation trapping agent (e.g. phenol, anisole, etc.).

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water,dichloromethane, alcohol (e.g. methanol, ethanol, etc.),tetrahydrofuran, dioxane, acetone, etc., or a mixture thereof. A liquidbase or acid can be also used as the solvent.

The reaction temperature is not critical and the reaction is usuallycarried out under from cooling to heating.

(ii) REDUCTION

The reduction method applicable for this removal reaction may include,for example, reduction by using a combination of a metal (e.g. zinc,zinc amalgam, etc.) or a salt of chrome compound (e.g. chromouschloride, chromous acetate, etc.) and an organic or inorganic acid (e.g.acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.);and conventional catalytic reduction in the presence of a conventionalmetallic catalyst such as palladium catalysts (e.g. spongy palladium,palladium black, palladium oxide, palladium on carbon, colloidalpalladium, palladium on barium sulfate, palladium on barium carbonate,palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reducednickel, nickel oxide, Raney nickel, etc.), platinum catalysts (e.g.platinum plate, spongy platinum, platinum black, colloidal platinum,platinum oxide, platinum wire, etc.), and the like.

In case that the catalytic reduction is applied, the reaction ispreferably carried out around neutral condition.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, alcohol (e.g.methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, aceticacid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), andthe like, or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under from cooling to warming.

The removal reaction can be selected according to the kind of hydroxyprotective group to be removed.

(6) PROCESS 6

The compound (I-h) or salts thereof can be prepared by subjecting thecompound (I-g) or salts thereof to a removal reaction of thecarboxy-protective group(s) in R_(g) ¹ and/or R_(g) ².

Suitable salts of the compounds (I-g) and (I-h) may be the same as thosefor the compound (I).

This reaction is usually carried out by a conventional method such ashydrolysis, reduction and the like.

The method of hydrolysis and reduction, and the reaction conditions(e.g. reaction temperature, solvent etc.) are substantially the same asthose illustrated for removal reaction of the hydroxy-protective groupof the compound (I-a) in Process 5, and therefore are to be referred tosaid explanation.

The object compound (I) obtained according to the Processes 1 to 6 canbe isolated and purified in a conventional manner, for example,extraction, precipitation, fractional crystallization,recrystallization, chromatography, and the like.

Methods A to C for preparing the new starting compounds (II) and (IV) orsalts thereof are explained in detail in the following.

(A) METHOD A

The compound (II) or salts thereof can be prepared by reacting thecompound (V) or salts thereof with the compound (VI) or salts thereof.

Suitable salts of the compound (V) may be salts with bases such as thosegiven for the compound (I).

Suitable salts of the compound (VI) may be the same acid addition saltsas those for the compound (I).

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as dichloromethane,pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran,etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under from warming to heating.

(B) METHOD B

The compound (II) or salts thereof can be prepared by reducing the nitrogroup of the compound (VII) or salts thereof.

Suitable salts of the compound (VII) may be the same as those for thecompound (I).

The method of reduction and the reaction conditions (e.g. reactiontemperature, solvent, etc.) are substantially the same as thoseillustrated in Process 2, and therefore are to be referred to saidexplanation.

(C) METHOD C

The compound (IV) or salts thereof can be prepared by reacting thecompound (VIII) or its reactive derivative at the carboxy group, orsalts thereof with the compound (VI) or salts thereof.

Suitable salts of the compound (VIII) may be the same as those for thecompound (I).

Suitable reactive derivative of the compound (VIII) may include an acidhalide, an acid anhydride, an activated amide, an activated ester, andthe like.

The suitable example may be an acid chloride; an acid azide; a mixedacid anhydride with an acid such as substituted phosphoric acid (e.g.dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid etc.),dialkylphosphorous acid, lower alkanesulfonic acid (e.g. methanesulfonicacid, ethanesulfonic acid, etc.), sulforous acid, thiosulfuric acid,sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g.pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid ortrichloroacetic acid, etc.) or aromatic carboxylic acid (e.g. benzoicacid, etc.); a symmetrical acid anhydride; an activated amide withimidazole, 4-substituted imidazole, dimethylpyrazole, triazole ortetrazole; or an activated ester (e.g. cyanomethyl ester, methoxymethylester, dimethyliminomethyl [(CH₃)₂ N³⁰ ═CH--] ester, vinyl ester,propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester,trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester,phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester,p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridylester, piperidyl ester, 8-quinolyl thioester, etc.), or an ester with aN-hydroxy compound (e.g. N,N-dimethylhydroxylamine,1-hydroxy-2-[1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide,1-hydroxy-6-chloro-1H-benzotriazole, etc.), and the like. These reactivederivatives can optionally be selected from them according to the kindof the compound (VIII) to be used.

When the compound (VIII) is used in free acid from or its salt form inthe reaction, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N-carbonylbis-(2-methylimidazole);pentamethyleneketeneN-cyclohexylimine; diphenylketene-N-cyclohexylimine;ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethylpolyphosphate; isopropyl polyphosphate; phosphorus oxychloride(phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalylchloride; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, phosphorus oxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic ororganic base such as those given in the explanation of Process 3.

The reaction is usually carried out in a conventional solvent which doesnot adversely influence the reaction such as water, methanol, ethanol,acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylenechloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide,pyridine, etc. or a mixture thereof.

The reaction temperature is not critical, and the reaction is usuallycarried out under warming to heating.

The object quinazoline derivatives (I) stimulate presynaptic(neuronal)and/or postsynaptic(vascular) dopamine receptors that mediate inhibitionof neurogenic release of catecholamine and/or dilatation of renalvasculature and remission of parkinsonism, respectively. Quinazolinederivatives (I) effect on the cardiovascular system as a consequence ofits interaction with dopaminergic and adrenergic receptors.

The object compound (I) and pharmaceutically acceptable salts thereof ofthe present invention are novel and display dopamine receptorstimulating effects; 5-HT receptor antagonism, especially 5-HT₂ receptorantagonism; α₁ receptor antagonist; and the like, and are useful as adopamine receptor agonist; 5-HT receptor antagonist, especially 5-HT₂receptor antagonist; α₁ receptor antagonist; and the like, for treatingor preventing hypertension and other cardiovascular disorders (e.g.angina pectoris, congestive heart failure, myocardial infarction, etc.);Parkinsonism; hyperprolactinemia; disorders of peripheral perfusion suchas Raynaud's phenomenon, Burger's diseases, and intermittentclaudication; thrombotic and/or smooth muscle cell proliferative diseasesuch as restenosis after percutaneous transluminal coronary angioplasty;hypercholesterolemia; urinary disturvance; and the like.

The compound (I) and pharmaceutically acceptable salts thereof may bealso useful as a adrenolytic, tranquilizer, sedative, anti-emetic,hypothermic, skeletal muscle relaxant, anti-inflammatory, hypoglycemic,or anti-viral agent.

Now in order to show the utility of the object compound (I) andpharmaceutically acceptable salts, the test data on dopamine receptorstimulating effects of the representative compound of the compound (I)of this invention are shown in the following.

TEST COMPOUND

Compound A [The product of Example 2]

Compound B [The product of Example 12]

Test 1 [Dopamine receptor (DA₂ receptor) binding assay]

TEST METHOD 1

The affinity for DA₂ receptor of a Test Compound was determinedfollowing in vitro receptor binding assays.

Male rats weighing 150-300g were decapitated and the striatum weredissected from their brains. The tissue was homogenized in 30 volumes ofbuffer which consisted of 50 mM Tris-HCl (pH 7.4 at 25° C.), 120 mMsodium chloride, 5 mM potassium chloride, 1 mM calcium chloride, 1 mMmagnesium chloride, 10 μM pargirine, and 0.1% ascorbic acid. Thehomogenate was centrifuged at 50,000 g for 15 minutes. The pellet wasresuspended in 30 volumes of the buffer. The tissue suspension wascentrifuged and suspended again in the same way.

Incubation tubes received 100 μl of [phenyl-4-³ H]spiperone, 100 μl ofthe Test Compound and 0.8 ml of tissue suspension during binding assays.The concentration of [phenyl-4-³ H]spiperone was 0.2 nM. The finaltissue concentration of rat striatum was 160 μg/ml. The tubes wereincubated at 37° C. for 10 minutes, and then filtered under vacuumthrough Whatman GF/B filters and washed three times with 3 ml ofice-cold buffer. The filters were counted by liquid scintillationcounter.

Specific binding of the [³ H]spiperone was determined in the presence of1 μM butaclamol. The IC₅₀ value of the Test Compound was calculated fromthe data of [³ H]spiperone binding in the presence of 10⁻⁹ M, 10⁻⁸ M,10⁻⁷ M and 10⁻⁶ M Test Compound.

TEST RESULT 1

    ______________________________________                                        Test Compound  IC.sub.50 (M)                                                  ______________________________________                                        Compound A     8.1 × 10.sup.-9                                          ______________________________________                                    

Test 2 [Inhibition of reserpine-induced DOPA accumulation]

TEST METHOD 2

Male SD rats weighing 300-400 g were used in this test. Rats werepretreated with reserpine (1 mg/kg, S.C.) 17-19 hours before sacrificeand then fasted. Test Compound was given orally to the rats 2 hoursbefore sacrifice. [m-Hydroxybenzylhydrazine (100 mg/kg, i.p.) was given30 minutes before sacrifice.] Each rat was exposed to microwaves using ahead-focus microwave applicator for 1.5 seconds. The whole brain wasremoved and further separated into the striatum.

DOPA was determined as follows; the striatum was homogenized in 9volumes of 0.1N perchloric acid solution (0.4% EDTA.2Na). The homogenatewas centrifuged at 10,000 rpm for 1 minutes. The supernatant was appliedto high performance liquid chromatography.

TEST RESULT 2

    ______________________________________                                        Test Compound dose (mg/kg)                                                                             Inhibition (%)                                       ______________________________________                                        Compound A    3.2        33                                                   ______________________________________                                    

Test 3 [Hypotensive effect on spontaneous hypertensive rats]

TEST METHOD 3

15 to 25-Week-old male spontaneous hypertensive rats with mean arterialblood pressure of about 160-200 mmHg, weighing 300-350 g, were used. Theanimals were cannulated in the left femoral artery and the mean bloodpressure and heart rate were measured with a pressure-transducer. Theanimals were deprived of food for about 18 hours before oral dosing. TheTest Compound was suspended in 0.5% methylcellulose, and given orally.

TEST RESULT 3

The maximum decrease of blood pressure (%) is shown in Table.

    ______________________________________                                                                Maximum decrease of                                   Test Compound                                                                             dose (mg/kg)                                                                              blood pressure (%)                                    ______________________________________                                        Compound A  0.32        34                                                    ______________________________________                                    

Test 4 : [Serotonin (5HT) antagonistic activity]

TEST METHOD 4

Male normotensive Wistar rats, weighing 250 to 300 g, were anesthetizedby pentabarbital Na (50 mg/kg, i.p.) and the common carotid artery andexternal jugular vein were cannulated, respectively, for blood pressuremeasurement with a pressure-transducer and for drug administration.

The trachea was cannulated, and the rats were pithed by inserting asteel rod into the spiral canal via an eye orbit and immediatelyartifically respired. Atropine at 1 mg/kg and d-tubocurarine at 1 mg/kgwas intraveneouly administered through the cannula. To evaluate theantagonistic effect of test compounds, pressor response to iv injectionof 5HT (3.2, 10, 32 μg/kg) were obtained before and 10 min after i.v.doses of test compounds. Each pressor response curve to 5HT was plotted,and the antagonistic potency of test compound was expressed as thechange of the 5HT ED₃₀ values (i.v. doses of 5HT producing a 30 mmHgincrease in diastolic blood pressure).

TEST RESULT

    ______________________________________                                                             ED.sub.30 (μg/kg)                                     Test compound                                                                              dose (g/kg)   pre      post                                      ______________________________________                                        Compound A   0.32          14       25                                        Compound B   0.32           8       32                                        ______________________________________                                    

Test 5 [α1-adrenoceptor binding assay]

TEST METHOD 5

Male Wistar rats (200-250 g) were killed by decapitation and the brainwas placed in ice-cold buffer (0.25M sucrose, 5 mM Tris/HCl, 1 mM MgCl₂,pH 7.5). Whole brain was homogenized in 10-20 volume (w/v) of ice-coldbuffer for 20 strokes using a motor-drived Teflon-glass homogenizer. Thehomogenate was centrifuged at 1,000 g for 10 min at 4° C., and thepellet was discarded. The supernatant was centrifuged at 30,000 g for 20min at 4° C. The pellet obtained was washed by resuspension in 20 mlice-cold 50 mM Tris/HCl, 10 mM MgCl₂ buffer (pH 7.5) and recentrifugedat 30,000 g for 20 min at 4° C. The final pellet was resuspended in 15volumes of original wet weight of 50 mM Tris/HCl, 10 mM MgCl₂ buffer (pH7.5) for use in the assays.

For ³ H-Prazosin binding to rat brain, membrane suspensions preparedfrom rat whole brain (0.3-0.4 mg protein) were incubated by constantshaking for 20 min at 30° C. with ³ H-Prazosin (0.6 μM) and increasingconcentrations of test compounds (10⁻⁶ - 10⁻⁹ M) in a total volume of550 μl of 50 mM Tris/HCl, 10 mM MgCl₂ buffer containing 0.1 mg/ml bovineserum albumin (pH 7.5). The incubation, which was performed induplicate, was terminated by adding 4 ml of ice-cold 50 mM Tris/HCl, 10mM MgCl₂ buffer (pH 7.5) followed by rapid filtration through WhatmanGF/C glass filter disks. The filter disks were washed 3 times with 4 mlice-cold 50 mM Tris/HCl, 10 mM MgCl₂ buffer (pH 7.5), and dried for 2hours at 80° C. These filter disks were counted by liquid scintillationcounter with an efficacy of 40%. Nonspecific binding was defined asnondisplaceable binding in the presence of 10 μM phentolamine, whilespecific binding was defined as the difference between total and nonspecific binding. The concentration of the test compound inhibiting 50%of the specific binding of ³ H-Prazosin was calbulated by log profitanalysis of the binding data.

TEST RESULT 5

    ______________________________________                                        Test Compound  IC.sub.50 (M)                                                  ______________________________________                                        Compound A     2.0 × 10.sup.-8                                          Compound B     3.8 × 10.sup.-8                                          ______________________________________                                    

For therapeutic administration, the object compound (I) and thepharmaceutically acceptable salts thereof of the present invention areused in the form of conventional pharmaceutical preparation whichcontains said compound, as an active ingredient, in admixture withpharmaceutically acceptable carriers such as an organic or inorganicsolid or liquid excipient which is suitable for oral, parenteral andexternal administration. The pharmaceutical preparations may be in solidform such as tablet, granule, powder, capsule, or liquid form such assolution, suspension, syrup, emulsion, lemonade, and the like.

If needed, there may be included in the above preparations auxiliarysubstances, stabilizing agents, wetting agents and other commonly usedadditives such as lactose, stearic acid, magnesium stearate, terra alba,sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, oliveoil, cacao butter, ethylene glycol, tartaric acid, citric acid, fumaricacid, and the like.

While the dosage of the compound (I) may vary from and also depend uponthe age, conditions of the patient, a kind of diseases, a kind of thecompound (I) to be applied, etc. In general, amount between about 0.001mg and about 300 mg, preferably about 0.1 mg to about 50 mg per day maybe administered to a patient. An average single dose of about 0.001 mg,0.01 mg, 0.03 mg, 0.1 mg, 0.3 mg, 0.6 mg, 1.0 mg, 3.0 mg, 10.0 mg, 50.0mg, 100.0 mg, of the object compound (I) of the present invention may beused as adrenolytic, hypotensive, cardiovascular, tranquilizer,sedative, anti-emetic, hypothermic, skeletal muscle relaxant,anti-inflammatory, and anti-viral agents.

The following Preparations and Examples are given for the purpose ofillustrating this invention in more detail.

PREPARATION 1

1) A mixture of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridinehydrochloride (11.5 g), 4-chlorobutyronitrile (5.7 g), sodium iodide(7.5 g), potassium carbonate (13.8 g) and 2-butanone (100 ml) wasstirred under reflux for 8 hours. After filtration and evaporation ofthe filtrate, the crude residue was dissolved in ethyl acetate, washedwith brine, dried over magnesium sulfate and evaporated to give an oil(15.6 g). The oil was chromatographed on silica gel (450 g) to affordcrystals of4-[4-[4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]butyronitrile(13.0g).

mp : 71°-73° C.

IR (Nujol) : 2900, 1490, 1400 cm⁻¹

NMR (CDCl₃, δ) : 1.84-1.97 (2H, m), 2.43-2.65 (6H, m), 2.70 (2H, t,J=5Hz), 3.17 (2H, t, J=5Hz), 6.02-6.09 (1H, m), 7.27-7.34 (4H, m)

2) To a stirred solution of4-[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]butyronitrile (13.0g) in dry tetrahydrofuran (130 ml) was added 1M solution of lithiumaluminum hydride in tetrahydrofuran (60 ml), and the mixture was stirredfor 1 hour. After saturated aqueous ammonium chloride solution (10 ml)was added with stirring, the organic layer was separated by decantation,dried over magnesium sulfate and evaporated to dryness to give an oil of4-[4-[4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]butylamine (7.18g).

IR (Neat) : 3250, 2930, 1660 cm⁻¹

NMR (CDCl₃, δ) : 1.47-1.68 (4H, m), 2.14 (2H, br s), 2.42-2.78 (6H, m),3.14 (2H, t, J=5Hz), 3.78 (2H, t, J=5Hz), 6.03-6.09 (1H, m), 7.23-7.37(4H, m)

PREPARATION 2-1)

A mixture of 4-nitroisatonic anhydride (0.62 g),4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butylamine (0.83 g) andchloroform (10 ml) was stirred under reflux for 1 hour. Afterevaporation of the solvent, the crude residue was chromatographed onsilica gel to give crystals of2-amino-4-nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide(0.56 g).

mp : 135°-137° C.

IR (Nujol) : 3450, 3300, 1630 cm⁻¹

NMR (CDCl₃, δ) : 1.72-1.82 (4H, m), 2.50-2.60 (4H, m), 2.73 (2H, t,J=5Hz), 3.17 (2H, t, J=5Hz), 3.47 (2H, d, J=5Hz), 6.75 (2H, s),6.00-6.07 (1H, m), 7.16-7.43 (8H, m), 8.12 (1H, br s)

PREPARATION 2-2)

2-Amino-N-[4-{4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl}butyl]benzamidewas obtained in 94.7% yield in substantially the same manner as that ofPreparation 2-1).

mp 140°-142° C.

IR (Nujol) : 3320, 3260, 1605 cm⁻¹

NMR (CDCl₃, δ) : 1.77 (4H, t, J=5Hz), 2.50-2.62 (4H, m), 2.72 (2H, t,J=5Hz), 3.12-3.18 (2H, m), 3.45 (2H, d, J=5Hz), 5.52 (2H, br s),6.02-6.07 (1H, m), 6.51 (1H, t, J=8Hz), 6.65 (1H, d, J=5Hz), 6.95 (1H,br s), 7.14 (1H, t, J=8Hz), 7.25-7.31 (5H, m)

The following compounds were obtained in substantially the same manneras that of Preparation 2-1).

PREPARATION 3

2-Amino-5-chloro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide

IR (Nujol) : 3400 (br), 1620, 1570 cm⁻¹

PREPARATION 4

2-Amino-4-chloro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide

NMR (CDCl₃, δ) : 1.65-1.80 (4H, m), 2.45-2.60 (4H, m), 2.70 (2H, t,J=5Hz), 3.15 (2H, dd, J=6Hz, 3Hz), 3.45 (2H, dd, J=12Hz, 6Hz), 5.60 (1H,br s), 6.05-6.10 (1H, m), 6.40 (1H, dd, J=8Hz, 1.5Hz), 6.60 (1H, d,J=1.5Hz), 7.20 (1H, d, J=8Hz), 7.25-7.40 (7H, m)

PREPARATION 5-1)

A solution N-(4-bromobutyl)phthallmide (0.85 g),4-(4-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (0.63 g) andtriethylamine (0.91 g) in dry acetonitrile (10 ml) was refluxed for 3hours. After evaporation of the solvent, crude residue was dissolved inethyl acetate, washed with water, sat. ammonium chloride solution andbrine successively, dried over magnesium sulfate and evaporated to givea yellow solid ofN-[4-{4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl}-butyl]phthalimide(0.99 g).

NMR (CDCl₃, δ) : 1.60-1.85 (4H, m), 2.35 (3H, s), 2.50-2 60 (4H, m),2.70 (2H, t, J=5Hz), 3.10-3.20 (2H, m), 3.25 (2H, t, J=7Hz), 5.95-6.05(1H, m), 7.10 (2H, d, J=8Hz), 7.25 (2H, d, J=8Hz), 7.70-7.85 (4H, m)

PREPARATION 5-2)

A solution ofN-[4-{4-{4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl}butyl]phthalimide(0.98 g), hydrazine hydrate [0.17 g) in methanol (10 ml) was stirredunder reflux for 4 hours. After evaporation of the solvent, the cruderesidue was mixed with chloroform and 1N sodium hydroxide. Thechloroform layer was separated, dried over magnesium sulfate andevaporated to give an oil of4-[4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl]butylamine (0.96g).

NMR (CDCl₃, δ) : 1.55-1.70 (4H, m), 2.30 (3H, s), 2.45-2.60 (4H, m),2.70 (2H, t, J=5Hz), 3.60-3 70 (4H, m), 5.95-6.05 (1H, m), 7.10 (2H, d,J=8Hz), 7.25 (2H, d, J=8Hz)

The following compounds were obtained in substantially the same manneras that of Preparation 2-1).

PREPARATION 5-3)

2-Amino-N-[4-{4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl}butyl]benzamide

NMR (CDCl₃, δ) : 1.65-1.75 (4H, m), 2.35 (3H, s), 2.45-2.60 (4H, m),2.70 (2H, t, J=5Hz), 3.10-3.15 (2H, m), 5.5 (2H, br s), 5.95-6.05 (1H,m), 6.50 (1H, td, J=8Hz, 1.5Hz), 6.65 (1H, dd, J=8Hz, 1.5Hz), 7.00 (1H,br s), 7.05-7.30 (6H, m)

PREPARATION 6

2-Amino-N-[4-{4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl}butyl]benzamide

NMR (CDCl₃, δ) : 1.65-1.75 (4H, m), 2.45-2.60 (4H, m), 2.70 (2H, t,J=5Hz), 3.15 (2H, dd, J=6Hz, 2.5Hz), 3.40-3.50 (2H, m), 5.45-5.55 (2H,br s), 5.55-5.65 (1H, m), 6.50 (1H, td, J=8Hz, 1.5Hz), 6.65 (1H, dd,J=7Hz, 1Hz), 6.40-7.05 (3H, m), 7.15 (1H, td, J=8Hz, 1.5Hz), 7.25-7.40(2H, m)

PREPARATION 7-1)

To a solution of 2-amino-4-sulfamoylbenzoic acid (1.32 g) in 2N sodiumhydroxide (6 ml) was added dropwise ethyl chloroformate (1.9 ml) and 2Nsodium hydroxide on an ice bath. After stirring for 3 hours, thereaction mixture was acidified with 1N hydrochloric acid, extracted withethyl acetate. Combined organic extracts were washed in turn with waterand brine, dried over magnesium sulfate and evaporated to give anamorphous of 2-ethoxycarbonylamino-4-sulfamoylbenzoic acid (1.99 g).

NMR (CDCl₃, δ) : 1.33 (3H, t, J=7Hz), 2.80 (2H, br s), 4.20 (2H, q,J=7Hz), 7.70 (1H, dd, J=8Hz, 2Hz), 8.20 (2H, m), 9.00 (1H, d, J=2Hz)

PREPARATION 7-2)

2-Ethoxycarbonylamino-4-sulfamoyl-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamidewas obtained in substantially the same manner as that of Preparation9-1).

NMR (CDCl₃, δ) : 1.25 (3H, t, J=6Hz), 1.70-2.30 (4H, m), 2.80-3.00 (2H,m), 3.10-3.60 (6H, m), 4.10 (2H, d, J=6Hz), 6.00-6.10 (1H, m), 7.30-7.40(5H, m), 7.50 (1H, d, J=7H), 8.10-8.20 (1H, m), 8.60 (1H, d, J=1.5Hz)

PREPARATION 8

2-Amino-5-nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamidewas obtained in substantially the same manner as that of Preparation2-1).

NMR (CDCl₃, δ) : 1.70-1.85 (4H, m), 2.35-2.45 (2H, m), 2.55 (2H, t,J=6Hz), 2.70 (2H, t, J=6Hz), 3.25 (2H, dd, J=6Hz, 2.5Hz), 3.45 (2H, dd,J=12Hz, 6Hz), 5.95-6.00 (1H, m), 6.35-6.45 (2H, br s), 6.45 (1H, d,J=9Hz), 7.15-7.35 (5H, m), 7.85 (1H, dd, J=9Hz, 2.5Hz), 8.10-8.20 (1H,m), 8.25 (1H, d, J=2.5Hz)

PREPARATION 9-1)

To a solution of 4-methoxy-2-nitrobenzoic aid (1.3 g) in drytetrahydrofuran (15 ml) was added thionyl chloride (2.86 ml) and themixture was refluxed for 1.5 hours. After evaporation of the solvent andexcess thionyl chloride, the residue was dissolved in dry methylenechloride (10 ml), which was added to a solution of4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butylamine hydrochloride(0.87 g) and triethylamine (2.0 g) in dry methylene chloride (20 ml) onan ice-bath. After stirring for 1.5 hours, the reaction mixture waswashed with water, sat. sodium bicarbonate solution and brinesuccessively, dried over magnesium sulfate and evaporated. The cruderesidue was chromatographed on silica gel (20 g, chloroform and methanol(50:1-9:1, V/V) as an eluent] to give an oil of4-methoxy-2-nitro-N-[4-(4-phenyl1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide(1.2 g).

NMR (CDCl₃, δ) : 1.70-1.85 (4H m) 2.20-2.35 (2H, m), 2.45-2.55 (2H, m),2.60 (2H, t, J=6Hz), 3.00 (2H, dd, J=6Hz, 3Hz), 3.40-3.50 (2H, m), 3.60(3H, s), 5.75-5.85 (1H, m), 6.80 (1H, dd, J=9Hz, 2Hz), 7.15-7.35 (7H,m), 8.80 (1H, br s)

PREPARATION 9-2)

A mixture of4-methoxy-2-nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide(1 g), tin(II) chloride (1.39 g) and ethanol (20 ml) was stirred underreflux for 0.5 hour. After cooling, sat. sodium bicarbonate solution wasadded and the mixture was diluted with chloroform (50 ml). A chloroformlayer was separated, washed in turn with water and brine, dried overmagnesium sulfate and evaporated. Crude residue (0.93 g) waschromatographed on a silica gel [13 g, chloroform and methanol(50:1-20:1, V/V) as an eluent] to give2-Amino-4-methoxy-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide(0.54 g).

NMR (CDCl₃, δ) : 1.65-1.75 (4H, m), 2.50-2.65 (4H, m), 2.70 (2H, t,J=5Hz), 3.15 (2H, dd, J=6Hz, 2Hz), 3.35-3.45 (2H, m), 3.70 (3H, s), 5.70(1H, br s), 6.00-6.10 (2H, m), 6.90 (1H, br s), 7.20-7.40 (7H, m)

PREPARATION 10

2-Amino-N-[4-[4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamidewas obtained in substantially the same manner as that of Preparation2-1).

NMR {CDCl₃, δ) : 1.65-1.80 (4H, m), 2.55-2.65 (4H, m), 2.80 (2H, t,J=5Hz), 3.25 (2H, dd, J=5Hz, 2.5Hz), 3.45 (2H, dd, J=12Hz, 6Hz), 5.50(1H, br s), 6.00-6.10 (1H, m), 6.55 (1H, td, J=7.5Hz, 1Hz), 6.65 (1H,dd, J=8Hz, 1.5Hz), 7.10 (2H, br s), 7.15 (1H, td, J=8Hz, 1.5Hz),7.15-7.40 (6H, m)

PREPARATION 11-1)

A mixture of 4-methoxycarbonyl-3-nitrobenzoic acid (2.25 g), 1M boranein tetrahydrofuran solution (50 ml) and dry tetrahydrofuran (45 ml) wasstirred at room temperature for 48 hours. To this mixture, methanol (2ml) and 1N hydrochloric acid (10 ml) were added and then the solventswere evaporated off. The crude residue was taken up with ethyl acetate,washed in turn with water and sat. sodium bicarbonate solution, driedover magnesium sulfate and evaporated to give an oil which waschromatographed on silica gel. Elution with toluene-chloroform (1:1)gave methyl 4-hydroxymethyl-2-nitrobenzoate (1.85 g).

NMR (CDCl₃, δ) : 3.95 (3H, s), 4.82 (2H, s), 7.63 (1H, dd, J=8H, 2Hz),7.70 (1H, d, J=8Hz), 7.88 (1H, d, J=2Hz)

PREPARATION 11-2)

A mixture of methyl 4-hydroxymethyl-2-nitrobenzoate (1.49 g), thionylchloride (1.08 g), dry pyridine (0.1 g), dry ether (70 ml) and drytetrahydrofuran (20 ml) was stirred overnight. The reaction mixture waswashed in turn with 1N hydrochloric acid and sat. sodium bicarbonatesolution, dried over magnesium sulfate and evaporated to give methyl4-chloromethyl-2-nitrobenzoate (1.60 g).

NMR (CDCl₃, δ) : 3.93 (3H, s), 4.65 (2H, s), 7.70 (1H, dd, J=8Hz, 2Hz),7.77 (1H, d, J=8Hz), 7.95 (1H, d, J=2Hz)

PREPARATION 11-3)

A mixture of methyl 4-chloromethyl-2-nitrobenzoate (1.6 g), 28% sodiummethoxide-methanol solution (2.5 ml) in methanol [16 ml) was stirredunder reflux for 24 hours. To this mixture, water (5 ml) was added andthe mixture was stirred for 2 hours, acidified with 1N hydrochloricacid, extracted with ethyl acetate. The combined organic extract waswashed with water, dried over magnesium sulfate and evaporated to give4-methoxymethyl-2-nitrobenzoic acid (0.84 g).

NMR (CDCl₃, δ) : 3.48 (3H, s), 4.60 (2H, s), 7.63 (1H, dd, J=8Hz, 2Hz),7.80 (1H, d, J=2Hz), 7.90 (1H, d, J=8Hz)

PREPARATION 11-4)

2-Nitro-4-methoxymethyl-N-[4-(4-methyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamidewas obtained in substantially the same manner as that of Preparation9-1).

NMR (CDCl₃, δ) : 1.75 (4H, m), 2.25 (2H, m), 2.50 (2H, m), 2.65 (2H, m),3.02 (2H, m), 3.32 (3H, s), 3.47 (2H, m), 4.22 (2H, s), 5.73 (1H, m),7.1-7.4 (7H, m), 7.68 (1H, s), 8.90 (1H, m)

PREPARATION 11-5)

2-Amino-4-methoxymethyl-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamidewas obtained in substantially the same manner as that of Preparation9-2).

NMR (CDCl₃, δ) : 1.70 (2H, m), 1.95 (2H, m), 2.55 (4H, m), 2.72 (2H, m),3.15 (2H, m), 3.32 (3H, s), 3.45 (2H, m), 4.30 (2H, s), 6.03 (1H, m),6.45 (1H, dd, J=8Hz, 2Hz), 6.60 (1H, d, J=2Hz), 7.00 (1H, m), 7.2-7.4(6H, m)

PREPARATION 12-1)

4-Carbamoyl-2-nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamidewas obtained in substantially the same manner as that of Preparation9-1).

NMR (DMSO-d₆, δ) :1.70 (4H, m), 1.85 (2H, m), 2.60 (2H, m), 2.75 (2H,m), 3.25 (2H, m), 3.40 (2H, m), 6.30 (1H, m), 7.35-7.60 (4H, m), 7.83(1H, d, J=8Hz), 7.95 (1H, m), 8.35 (1H, dd, J=8Hz, 2Hz), 8.50 (1H, m),8.60 (1H, m), 8.95 (1H, m)

PREPARATION 12-2)

2-Amino-4-carbamoyl-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamidewas obtained in substantially the same manner as that of Preparation9-2).

NMR [DMSO-d₆, δ) : 1.55 (4H, m), 2.35-2.7 (6H, m), 3.05 (2H, m), 3.25(2H, m), 6.15 (1H, m), 6.50 (2H, m), 7.00 (1H, d, J=8Hz), 7.2-7.6 (8H,m), 7.90 (1H, br s), 8.37 (1H, m)

PREPARATION 13-1)

4-Morpholinocarbonyl-2-nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamidewas obtained in substantially the same manner as that of Preparation9-1).

IR (Nujol) : 1660, 1640 cm⁻¹

PREPARATION 13-2)

2-Amino-4-morpholinocarbonyl-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzanidewas obtained in substantially the same manner as that of Preparation9-2).

NMR (DMSO-d₆, δ) : 1.55 (4H, m), 2.35-2.65 (6H, m), 3.05 (2H, m), 3.25(2H, m), 3.60 (8H, m), 6.15 (1H, m), 6.50 (3H, m), 6.70 (1H, d, J=2Hz),7.2-7.6 (6H, m), 8.34 (1H, t, J=6Hz)

PREPARATION 14-1)

Methyl 4-morpholinomethyl-2-nitrobenzoate was obtained in substantiallythe same manner as that of the former part of Preparation 11-3).

NMR (CDCl₃, δ) : 2.50 (4H, m), 3.61 (2H, s), 3.75 (4H, m), 3.93 (3H, s),7.6-8.0 (3H, m)

PREPARATION 14-2)

4-Morpholinomethyl-2-nitrobenzoic acid was obtained in substantially thesame manner as that of the latter part of Preparation 11-3).

NMR (CDCl₃, δ) : 2.40 (2H, m), 2.51 (2H, m), 3.60 (4H, m), 7.7-7.9 (3H,m)

PREPARATION 14-3)

4-Morpholinomethyl-2-nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamidewas obtained in substantially the same manner as that of Preparation11-4).

NMR (CDCl₃, δ) : 1.83 (4H, m), 2.37 (4H, m), 2.95 (2H, m), 2.71 (2H, m),2.87 (2H, m), 3.25 (2H, m), 3.33 (2H, s), 3.50 (2H, m), 3.68 (4H, m),5.82 (1H, m), 7.2-7.4 (7H, m), 7.82 (1H, s), 8.49 (1H, m)

PREPARATION 14-4)

2-Amino-4-morpholinomethyl-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamidewas obtained in substantially the same manner as that of Preparation11-5).

NMR (CDCl₃, δ) : 1.75 (4H, m), 2.40 (4H, m), 2.65 (4H, m), 2.85 (2H, m),3.30 (2H, m), 3.33 (2H, s), 3.45 (2H, m), 3.70 (4H, m), 5.55 (2H, br s),6.02 (1H, m), 6.50 (1H, dd, J=8Hz, 1Hz), 6.64 (1H, s), 7.04 (1H, m),7.2-7.4 (6H, m)

PREPARATION 15

2-Amino-5-methoxycarbonyl-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamidewas obtained in substantially the same manner as that of Preparation2-1).

IR (CHCl₃) : 3500, 3350, 2940, 1700, 1640, 1615 cm⁻¹

PREPARATION 16-1)

A mixture of methyl 4-hydroxymethyl-2-nitrobenzoate (1.06 g) tritylchloride (1.67 g) in dry pyridine (20 ml) was stirred at 80° C. for 8hours. The reaction mixture was diluted with water, acidified with 6Nhydrochloric acid, and extracted with ethyl acetate. The combinedorganic extract was washed with 1N hydrochloric acid, saturated sodiumbicarbonate solution and brine successively, dried over magnesiumsulfate and evaporated to give an oil, which was crystallized frommethanol to afford methyl 2-nitro-4-trityloxymethylbenzoate (1.87 g)

NMR (CDCl₃, δ): 3.41 (3H, s), 4.32 (2H, s), 7.32 (9H, m), 7.50 (6H, m),7.64 (1H, dd, J=8, 1.5Hz), 7.72 (1H, d, J=8Hz), 7.85 (1H, d, J=1.5Hz)

PREPARATION 16-2)

2-Nitro-4-trityloxymethylbenzoic acid was obtained in substantially thesame manner as that of Preparation 11-3).

NMR (CDCl₃, δ): 4.23 (2H, s), 7.25 (9H, m), 7.43 (6H, m), 7.52 (1H, m),7.75 (2H, m)

PREPARATION 16-3)

2-Nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-4-trityloxymethylbenzamidewas obtained in substantially the same manner as that of Preparation11-4).

NMR (CDCl₃, δ): 1.80 (4H, m), 2.25 (2H, m), 2.55 (2H, m), 2.68 (2H, m),3.06 (2H, m), 3.49 (2H, m), 4.00 (2H, s), 5.76 (1H, m), 7.07 (5H, m),7.25-7.50 (17H, m), 7.70 (1H, s), 8.83 (1H, m)

PREPARATION 16-4)

2-Amino-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-4-trityloxymethylbenzamidewas obtained in substantially the same manner as that of Preparation11-5).

NMR (CDCl₃, δ):1.71 (4H, m), 2.57 (4H, m), 2.75 (2H, m), 3.19 (2H, m),3.45 (2H, m), 4.01 (2H, s), 5.60 (2H, brs), 6.05 (1H, m), 6.50 (1H, dd,J=8, 1.5Hz), 6.73 (1H, d, J=1.5Hz), 6.97 (1H, m), 7.15-7.40 (14H, m),7.47 (6H, m)

EXAMPLE 1-1)

A mixture of2-amino-4-nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide(0.52 g) and carbonyldiimidazole (0.43 g) in dry tetrahydrofuran (10 ml)was stirred under reflux for 2 hours. After evaporation of the solvent,the crude residue was crystallized and recrystallized from ethanol togive crystals of7-nitro-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione(0.32 g).

mp 170°-171° C.

IR (Nujol) : 3270, 1720, 1640 cm⁻¹

NMR (DMSO-d₆, δ): 1.42-1.72 (4H, m), 2.38-2.49 (4H, m), 2.61 (2H, t,J=5Hz), 3.07 (2H, d, J=5Hz), 3.97 (2H, t, J=5Hz), 6.11-6.17 (1H, m),7.19-7.43 (5H, m), 7.91-7.95 (2H, m), 8.15 (1H, d, J=8Hz)

EXAMPLE 1-2)

3-[4-{4-(4-Chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl}butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in 42.1% yield in substantially the same manner as that ofExample 1-1).

mp : 220° C. (dec.)

IR (Nujol) : 3100, 1705, 1650 cm⁻¹

NMR (DMSO-d₆, δ) : 1.56-1.82 (4H, m), 2.43-2.75 (6H, m), 3.10-3.20 (2H,m), 4.02 (2H, t, J=5Hz), 6.27-6.33 (1H, m), 7.32 (1H, t, J=8Hz),7.45-7.59 (5H, m), 7.75 (1H, t, J=8Hz), 8.03 (1H, d, J=8Hz)

EXAMPLE 2

To a stirred solution of7-nitro-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione(0.2 g) in ethanol (10 ml) was added. Stannous chloride (0.46 g) and themixture was refluxed for 30 minutes. After cooling, an aqueous sodiumbicarbonate was added to adjust the pH to 7 and inorganic salts werefiltered off through filter cell. The filter cake was washed with hotethanol. Combined filtrate and washings were evaporated and the cruderesidue was washed in turn with water and cold ethanol, and then driedto give crystals of7-hydroxyamino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione(85 mg).

mp : 187°-189° C.

IR (Nujol) : 3250, 1700 cm⁻¹

NMR (DMSO-d₆, δ) : 1.42-1.68 (4H, m), 2.38-2.52 (4H, m), 2.60 (2H, t,J=5Hz), 3.05 (2H, d, J=5Hz), 3.88 (2H, t, J=5Hz), 6.10-6.15 (1H, m),6.51 (1H, d, J=8Hz), 6.54 (1H, s), 7.30-7.45 (6H, m), 7.65 (1H, d,J=8Hz), 8.75 (1H, s), 9.15 (1H, s)

EXAMPLE 3

A mixture of7-nitro-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl-1,2,3,4-tetrahydroquinazoline-2,4-dione(0.34 g), tin[II) chloride (0.76 g) in ethanol (16 ml) was stirred underreflux for 1 hour. After cooling, 1N sodium hydroxide was added and thesolution was stirred. The organic layer was separated, dried overmagnesium sulfate and evaporated to give a solid (0.33 g), which wasrecrystallized from ethyl acetate-hexane to give7-amino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione(0.18 g).

mp : 250° C. [dec.)

IR (Nujol) : 3400, 3300, 3200, 1610, 1580, 1520 cm⁻¹

NMR (DMSO-d₆, δ) : 1.45-1.65 (2H, m), 1.70-1.90 (2H, m), 2.80 (2H, t,J=5Hz), 3.20 (4H, t, J=5Hz), 3.40 (2H, t, J=5Hz), 3.85 (2H, d, J=5Hz),5.80 (1H, s), 6.20 (1H, s), 7.25-7.50 (8H, m)

EXAMPLE 4

7-Acetamido-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 12 byusing acetyl chloride instead of methanesulfonyl chloride.

mp : 250°-251° C.

IR (Nujol) : 3450, 1710, 1630, 1605 cm⁻¹

NMR (DMSO-d₆, δ) : 1.45-1.72 (4H, m), 2.42-2.68 (6H, m), 3.10 (2H, d,J=5Hz), 3.43 (3H, s), 3.94 (2H, t, J=5Hz), 6.18 (1H, s), 7.22-7.50 (6H,m), 7.73 (1H, s), 7.88 (1H, d, J=10Hz)

EXAMPLE 5

3-[4-[4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-trifluoroacetamido-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 12 byusing trifluoroacetic anhydride instead.

mp: 263°-265° C. (dec.)

IR (Nujol) : 3200, 1710, 1650, 1620, 1560 cm⁻¹

NMR (DMSO-d₆, δ) : 1.45-1.75 (4H, m), 2.67 (2H, t, J=5Hz), 3.10 (2H, t,J=5Hz), 3.45-3.95 (6H, m), 6.07 (1H, s), 7.20-7.40 (6H, m), 7.65 (1H,s), 7.85 (1H, s)

EXAMPLE 6

7-Ethoxycarbonylamino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 12 byusing ethyl chloroformate instead.

mp : 200°-202° C. (dec.)

IR (Nujol) : 3270, 1700, 1640, 1550 cm⁻¹

NMR (DMSO-d₆, δ) : 1.05 (3H, t, J=8Hz), 1.20-1.47 (4H, m), 2.20 (4H, t,J=5Hz), 2.40 (2H, t, J=5Hz), 2.85 (2H, d, J=5Hz), 3.68 (2H, t, J=5Hz),3.97 (2H, q, J=8Hz), 5.93 (1H, s), 6.90-7.25 (6H, m), 7.35 (1H, s), 7.60(1H, d, J=8Hz)

EXAMPLE 7

A mixture of7-amino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione(0.39 g), ethyl isocyanate (0.21 g) in dry tetrahydrofuran (40 ml) wasstirred under reflux for 24 hours. After evaporation of the solvent, thecrude residue was chromatographed on silica gel [chloroform and methanol(50:1) as eluent] to give crystals (0.17 g). Recrystallization of thecrystals from isopropyl alcohol afforded7-(3-ethylureido)-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione(0.09 g).

mp : 220° C.

IR (Nujol) : 3330, 1700, 1640, 1540 cm⁻¹

NMR (DMSO-d₆, δ) : 1.02 (3H, t, J=8Hz), 1.42-1.70 (4H, m), 2.40-2.60(6H, m), 3.05 (2H, t, J=5Hz), 3.20 (2H, q, J=8Hz), 3.88 (2H, t, J=5Hz),6.12 (1H, s), 6.30 (1H, t, J=5Hz), 7.05 (1H, d, J=8Hz), 7.20-7.48 (5H,m), 7.76 (1H, d, J=8Hz), 9.02 (1H, s)

EXAMPLE 8

To a mixture of7-amino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione(0.39 g), acetic acid (5 ml) and water (10 ml) was added a solution ofpotassium cyanate 0.16 g) in water (2 ml) and the resulting mixture wasstirred for additional 3 hours. The reaction mixture was poured intowater and precipitated solid was filtered, washed in turn with water andethanol and dried to give3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-ureido-1,2,3,4-tetrahydroquinazoline-2,4-dione(0.12 g).

mp : 260° C.

IR (Nujol) : 3420, 1700, 1640, 1550 cm⁻¹

NMR (DMSO-d₆, δ) : 1.52-1.75 (4H, m), 2.72 (2H, t, J=5Hz), 3.00-3.50(4H, m), 3.72 (2H, t, J=5Hz), 3.92 (2H, t, J=5Hz), 6.18 (2H, s), 7.09(1H, d, J=8Hz), 7.32-7.53 (5H, m), 7.75 (1H, d, J=8Hz), 9.34 (1H, s)

EXAMPLE 9

7-Methylsulfonylamino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 12.

mp : 213°-215° C.

IR (Nujol) : 3250, 1700, 1640, 1590 cm⁻¹

NMR (DMSO-d₆, δ) : 1.25-1.50 (4H, m), 2.20 (6H, t, J=5Hz), 2.42 (2H, t,J=5Hz), 2.72 (3H, s), 3.70 (2H, t, J=5Hz), 5.93 (1H, s), 6.33 (1H, s),6.58 (1H, d, J=8Hz), 6.98-7.22 (5H, m), 7.55 (1H, d, J=8Hz), 7.65 (1H,s)

EXAMPLE 10

3-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]--trifluoroacetamido-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 12.

mp : 245° C.

IR (Nujol) : 3220, 1720, 1690, 1630, 1560 cm⁻¹

NMR (DMSO-d₆, δ) : 1.40-1.70 (4H, m), 2.41 (4H, t, J=5Hz), 2.57 (2H, t,J=5Hz), 3.05 (2H, d, J=5Hz), 3.94 (2H, t, J=5Hz), 6.10 (1H, s),7.17-7.43 (6H, m), 7.90 (1H, d, J=8Hz), 8.30 (1H, s)

EXAMPLE 11

6-Chloro-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 1-1).

mp : 214°-222° C.

IR (Nujol) : 1700, 1640, 1590 cm⁻¹

NMR (CDCl₃, δ) : 1.65-1.85 (4H, m), 2.60-2.75 (4H, m), 2.85 (2H, t,J=5Hz), 3.30 (2H, d, J=1.5Hz), 4.10 (2H, t, J=5Hz), 6.00-6.10 (1H, m),7.10 (1H, d, J=8.5Hz), 7.20-7.40 (5H, m), 7.50 (1H, dd, J=8.5Hz, 2.5Hz),8.05 (1H, d, J=2.5Hz)

EXAMPLE 12

A mixture of6-amino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione(390 mg), methanesulfonyl chloride (229 mg), potassium carbonate (276mg) and dry N,N-dimethylformamide (10 ml) was stirred for 1 hour at roomtemperature. The mixture was poured into water, neutralized with 1Nsodium hydroxide and extracted with ethyl acetate, and the extract waswashed with brine. The organic layer was dried and evaporated. The cruderesidue was chromatographed on a silica gel (50 g), eluting with 10%methanol in dichloromethane to give3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6-methylsulfonylamino-1,2,3,4-tetrahydroquinazoline-2,4-dione(292 mg). Recrystallization from ethyl acetate gave a crystal thereof(202 mg).

mp : 193°-195° C.

IR (Nujol) : 3230, 1700, 1620, 1505, 1305, 1140, 975, 820, 740 cm⁻¹

NMR (DMSO-d₆, δ) : 1.40-1.70 (4H, m), 2.42 (4H, t, J=5Hz), 2.60 (2H, t,J=5Hz), 2.93 (3H, s), 3.06 (2H, d, J=5Hz), 3.92 (2H, t, J=5Hz), 6.14(1H, s), 7.05-7.53 (7H, m), 7.78 (1H, s)

EXAMPLE 13

To a stirred solution of3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6-methylsulfonylamino-1,2,3,4-tetrahydroquinazoline-2,4-dione(158 mg) in methanol was added 10% hydrogen chloride in methanolsolution (123 mg) at 5° C. After stirring for 1 hour at 5° C., thesolution was evaporated. The residue was crystallized from isopropylalcohol-ethyl acetate to give3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6-methylsulfonylamino-1,2,3,4-tetrahydroquinazoline-2,4-dionehydrochloride [81 mg).

mp : 115° C. (dec.)

IR (Nujol) : 1700, 1650, 1140, 970, 740 cm⁻¹

NMR (DMSO-d₆, δ) : 1.60-1.87 (4H, m), 2.80 (2H, t, J=5Hz), 2.93 (3H, s),3.12-3.40 (6H, m), 3.93 (2H, t, J=5Hz), 6.20 (1H, s), 7.18-7.80 (8H, m),9.87 (1H, s)

The following compounds (Examples 14-16) were obtained in substantiallythe same manner as that of Example 1-1).

EXAMPLE 14

7-Chloro-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione

mp : 195°-197° C.

IR (Nujol) : 1720, 1650 cm⁻¹

NMR (CDCl₃, δ): 1.65-1.85 (4H, m), 2.60 (4H, m), 2.80 (2H, t, J=5Hz),3.20 (2H, d, J=3Hz), 4.10 (2H, t, J-7Hz), 6.05-6.10 (1H, m), 7.10 (1H,d, J=1.5Hz), 7.20 (1H, dd, J=8Hz, 1.5Hz), 7.25-7.40 (5H, m), 8.05 (1H,d, J=8.5Hz)

EXAMPLE 15

3-[4-{4-(4-Methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl}butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione

mp : 190°-192° C.

IR (Nujol) : 1720, 1650 cm⁻¹

NMR (CDCl₃, δ) : 1.65-1.85 (4H, m), 2.30 (3H, s), 2.55-2.65 (4H, m),2.25 (2H, t, J=5.5Hz), 3.15-3.25 (2H, m), 4.10 (2H, t, J=8Hz), 5.95-6.05(1H, m), 7.05 (2H, d, J=7Hz), 7.15 (2H, d, J=7Hz), 7.20-7.30 (2H, m),7.60 (1H, td, J=8Hz, 1Hz), 8.10 (1H, dd, J=8Hz, 1Hz), 9.50-9.70 (1H, brs)

EXAMPLE 16

3-[4-{4-(4-Fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl}butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione

mp : 196°-198° C.

IR (Nujol) : 1710, 1650 cm⁻¹

NMR (CDCl₃, δ) : 1.60-1.90 (4H, m), 2.50-2.60 (4H, m), 2.75 (2H, t,J=6Hz), 3.15-3.25 (2H, m), 4.10 (2H, td, J=7.5Hz, 1Hz), 5.95-6.05 (1H,m), 6.95-7.10 (3H, m), 7.20-7.35 (3H, m), 7.60 (1H, td, J=7Hz, 1Hz),8.10 (1H, dd, J=8Hz, 1.5Hz), 9.25-9.35 (1H, br s)

EXAMPLE 17

A mixture of2-ethoxycarbonylamino-4-sulfamoyl-N-[4-4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide(0.16 g), potassium hydroxide (54 mg) and ethanol (10 ml) was stirredunder reflux for 4 hours. After evaporation of the solvent, a smallamount of water was added and the solution was neutralized with 1Nhydrochloric acid. The precipitated materials were collected, trituratedwith ethanol and recrystallized from ethanol to give crystals of3-[4-4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-sulfamoyl-1,2,3,4-tetrahydroquinazoline-2,4-dione(63 mg).

mp : 213°-215° C.

IR (Nujol) : 1750, 1710, 1220, 1150 cm⁻¹

NMR (DMSO-d₆, δ) : 1.15 (3H, t, J=5Hz), 1.60-1.90 (4H, m), 2.65-3.00(2H, m), 3.10-3.50 (4H, m), 3.55-4.10 (4H, m), 4.05 (2H, q, J=5Hz),6.15-6.25 (1H, m), 7.30-7.50 (5H, m), 7.65 (1H, dd, J=7Hz, 1.5Hz), 7.80(1H, s), 8.20 (1H, d, J=7Hz)

EXAMPLE 18

6-Nitro-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 1-1).

mp : 184°-186° C.

IR (Nujol) : 1720, 1660, 1620, 1600 cm⁻¹

NMR (CDCl₃, δ) : 1.60-1.85 (4H, m), 2.55-2.65 (4H, m), 2.80 (2H, t,J=6Hz), 3.25 (2H, d, J=2.5Hz), 4.15 (2H, t, J=7.5Hz), 6.10 (1H, t,J=2.5Hz), 7.15-7 40 (6H, m), 8.40 (1H, dd, J=8Hz, 2.5Hz), 8.90 (1H, d,J=2.5Hz)

EXAMPLE 19

6-Amino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 3.

mp : 215° C. (dec.)

IR (Nujol) : 1710, 1640 cm⁻¹

NMR (CDCl₃ OD, δ) : 1.60-1.80 (4H, m), 2.50-2.65 (4H, m), 2.75 (2H, t,J=5Hz), 3.20 (2H, d, J=2Hz), 4.05 (2H, d, J=7Hz), 6.05-6.10 (1H, m),6.90-7.05 (2H, m), 7.25-7.40 (8H, m)

EXAMPLE 20

6-Hydroxyamino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 28.

mp : 234° C. (dec.)

IR (Nujol) : 1710, 1650, 1600 cm⁻¹

EXAMPLE 21

7-Methoxy-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 1-1).

mp : 210°-212° C.

NMR (CDCl₃, δ) : 1.65-1.85 (4H, m), 2.55-2.65 (4H, m), 2.80 (2H, t,J=5Hz), 3.20-3.30 (2H, m), 3.85 (3H, s), 4.05-4.15 (2H, t, J=7Hz),6.00-6.10 (1H, m), 6.50 (1H, d, J=2Hz), 6.75 (1H, dd, J=9Hz, 2Hz),7.25-7.40 (5H, m), 8.00 (1H, d, J=9Hz), 9.70 (1H, br s)

EXAMPLE 22

A mixture of7-methoxy-3-[4-[4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione(0.2 g), 47% hydrobromic acid (2.6 ml) and acetic acid (6 ml) wasrefluxed for 28 hours. After cooling, the reaction mixture was dilutedwith ethanol and the precipitated crystals were collected.Recrystallization from ethanol afforded7-hydroxy-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionehydrobromide (0.1 g).

mp : 278°-279° C.

IR (Nujol) : 3600-3300, 3300-3000, 1710, 1620 cm⁻¹

NMR (DMSO-d₆, δ): 1.55-1.85 (4H, m), 2.70-2.85 (2H, m), 3.15-3.40 (4H,m), 3.55-4.00 (4H, m), 6.15-6.25 (1H, br s), 6.55 (1H, d, J=1.5Hz), 6.60(1H, dd, J=9Hz, 1.5Hz), 7.30-7.55 (5H, m), 7.75 (1H, d, J=9Hz),9.50-9.70 (1H, br s)

The following compounds (Examples 23-25) were obtained in substantiallythe same manner as that of Example 1-1).

EXAMPLE 23

3-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1--yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione

mp : 186°-187° C.

IR (Nujol) : 1730, 1700, 1630 cm⁻¹

NMR (CDCl₃, δ) : 1.65-1.85 (4H, m), 2.55-2.65 (4H, m), 2.80 (2H, t,J=5Hz), 3.25 (2H, d, J=2.5Hz), 4.15 (2H, t, J=7Hz), 6.00-6.10 (1H, m),7.10 (1H, d, J=8Hz), 7.15-7.40 (6H, m), 7.55-7.65 (1H, m), 8.10 (1H, dd,J=8Hz, 1.5Hz)

EXAMPLE 24

7-Methoxymethyl-3-[4-[4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione

mp : 194°-198° C.

IR (Nujol) 1705, 1645, 1595 cm⁻¹

NMR (DMSO-d₆, δ) : 1.55 (4H, m), 2.40 (4H, m), 2.60 (2H, m), 3.03 (2H,m), 3.30 (3H, s), 3.90 (2H, m), 4.49 (2H, s), 6.12 (1H, m), 7.10 (2H,m), 7.2-7.4 (5H, m), 7.90 (1H, d, J=8Hz)

EXAMPLE 25

7-Carbamoyl-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionehydrochloride

mp : 273°-281° C.

IR (Nujol) : 3350, 3250, 1725, 1635, 1585 cm⁻¹

NMR (DMSO-d₆, δ) : 1.65 (4H, m), 2.75 (2H, m), 3.15 (2H, m), 3.5-4.0(6H, m), 6.10 (1H, m), 7.1-7.7 (8H, m), 7.90 (1H, d, J=8Hz), 8.15 (1H,s), 10.30 (1H, br s)

EXAMPLE 26

A mixture of7-carbamoyl-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione(0.15 g), 1N sodium hydroxide solution (5 ml) and ethanol (5 ml) wasstirred under reflux for 10 hours. After cooling, 1N hydrochloric acid(6 ml) was added and the precipitated crystals were collected to give7-carboxy-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione(0.15 g).

mp : 296°-305° C.

IR (Nujol) : 3250, 2700-2500, 1720, 1640 cm⁻¹

NMR (DMSO-d₆, δ) : 1.6-1.9 (4H, m), 2.80 (2H, m), 3.15 (4H, m), 3.80(2H, m), 3.95 (2H, m), 6.15 (1H, m), 7.3-7.6 (5H, m), 7.70 (1H, dd,J=8Hz, 2Hz), 7.80 (1H, d, J=2Hz), 8.03 (1H, d, J=8Hz)

EXAMPLE 27

7-Morpholinocarbonyl-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 1-1).

mp : 206°-210° C.

IR (Nujol) : 3200, 1715, 1645, 1625, 1600 cm⁻¹

NMR (CDCl₃, δ) : 1.75 (4H, m), 2.65 (4H, m), 2.85 (2H, m), 3.30 (2H, m),3.45 (2H, m), 3.65 (2H, m), 3.80 (4H, m), 4.10 (2H, m), 6.05 (1H, m),7.1-7.4 (7H, m), 8.12 (1H, d, J=8Hz)

EXAMPLE 28

To a stirred solution of7-nitro-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione(2.1 g) in 50% aqueous tetrahydrofuran (210 ml) was added ammoniumchloride (2.68 g) in water (27 ml). To this mixture was added zinc dust(1.65 g) by five portions over a period of 3 hours. The temperature wasraised at 32° C. during the reaction. After additional stirring for 2hours, the precipitated materials were filtered, washed with water andextracted with dimethylformamide (100 ml) under nitrogen. The organicextract was filtered and the filtered cake was washed withdimethylformamide (20 ml). The combined organic solution was dilutedwith water (24 ml), cooled in a refrigerator, and then treated withactive charcoal (1.05 g) and silica gel (2.1 g). The charcoal and silicagel were filtered off and washed with 80% aqueous dimethylformamide (5ml). To the combined solution was added dropwise cold water (96 ml) withstirring on an ice bath and the precipitated crystals were collected,washed with water, and then suspended in methanol (50 ml). To thismixture was added 10% hydrogen chloride in methanol (50 ml) and themixture was stirred for 1 hour. The precipitated crystals werecollected, washed with methanol, stirred with water, and then filteredand dried to give7-hydroxyamino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione(0.60 g).

mp : 265°-270° C.

EXAMPLE 29

7-Morpholinomethyl-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 1-1).

mp : 154°-156° C.

IR (Nujol) : 1710, 1640, 1595 cm⁻¹

NMR (DMSO-d₆, δ) : 1.55 (4H, m), 2.40 (8H, m), 2.60 (2H, m), 3.05 (2H,m), 3.52 (2H, s), 3.60 (4H, m), 3.92 (2H, m), 6.15 (1H, m), q 7.15 (2H,m), 7.2-7.45 (5H, m), 7.90 (1H, d, J=8Hz)

EXAMPLE 30

6-Methoxycarbonyl-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 1-1).

mp : 138° C.

EXAMPLE 31

6-Carboxy-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 26.

mp : 237° C.

NMR (DMSO-d₆, δ) : 1.68 (4H, br, s), 2.69 (2H, br s), 3.32 (6H, m), 3.95(2H, t, J=7Hz), 6.17 (1H, t, J=4Hz), 7.27 (1H, d, J=9Hz), 7.31 (1H, d,J=8Hz), 7.37 (2H, t, J=8Hz), 7.47 (2H, d, J=8Hz), 8.16 (1H, dd, J=2Hz,9Hz), 8.49 (1H, d, J=2Hz), 11.78 (1H, s)

EXAMPLE 32

6-Ethylsulfonylamino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 12.

mp : 210° C. (dec.)

IR (Nujol) : 3250, 1705, 1620, 1505, 1310, 1140 cm⁻¹

NMR (DMSO-d₆, δ) : 1.20 (3H, t, J=8Hz), 1.47-1.70 (4H, m), 2.40-2.50(4H, m), 2.62 (2H, d, J=5Hz), 3.05 (2H, q, J=8Hz), 3.09 (2H, d, J=5Hz),3.92 (2H, t, J=5Hz), 6.14 (1H, br s), 7.14-7.57 (7H, m), 7.80 (1H, s)

EXAMPLE 33

3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 1-1).

NMR (CDCl₃, δ) : 1.70 (4H, m), 2.57 (4H, m), 2.72 (2H, m), 3.16 (2H, m),4.10 (2H, m), 4.27 (2H, s), 6.01 (1H, m), 7.0-7.5 (21H, m), 7.71 (1H,s), 8.03 (1H, d, J=8Hz), 8.19 (1H, s)

EXAMPLES 34

A solution of3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione(1.1 g) and trifluoroacetic acid (10 ml) in dry methylene chloride (10ml) stirred at room temperature overnight. After evaporation of thesolvent, the crude residue was taken up with ethyl acetate, washed withsaturated sodium bicarbonate solution, dried over magnesium sulfate andevaporated to give a solid, which was chromatographed on a silica gel[elution with a mixed solvent of chloroform and methanol (20:1)] toafford crystals (0.53 g). Recrystallization of the crystals from ethanolgave7-hydroxymethyl-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione(0.16 g).

mp : 224°-226° C.

IR (Nujol) : 3250, 1700, 1620 cm⁻¹

NMR (DMSO-d₆, δ): 1.60 (4H, m), 2.43 (4H, m), 2.60 (2H, m), 3.07 (2H,m), 3.92 (2H, m), 4.58 (2H, d, J=7Hz), 5.48 (1H, t, J=7Hz), 6.15 (1H,m), 7.1-7.5 (7H, m), 7.89 (1H, d, J=8Hz)

EXAMPLE 35

7-Hydroxyamino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 1-1) orExample 17.

mp : 187°-189° C.

IR (Nujol) : 3250, 1700 cm⁻¹

NMR (DMSO-d₆, δ) : 1.42-1.68 (4H, m),. 2.38-2.52 (4H, m), 2.60 (2H, t,J=5Hz), 3.05 (2H, d, J=5Hz), 3.88 (2H, t, J=5Hz), 6.10-6.15 (1H, m),6.51 (1H, d, J=8Hz), 6.54 (1H, s), 7.30-7.45 (6H, m), 7.65 (1H, d,J=8Hz), 8.75 (1H, s), 9.15 (1H, s)

EXAMPLE 36

3-[4-[4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6-methylsulfonylamino-1,2,3,4-tetrahydroquinazoline-2,4-dionewas obtained in substantially the same manner as that of Example 1-1) orExample 17.

mp : 193°-195° C.

IR (Nujol) : 3230, 1700, 1620, 1505, 1305, 1140, 975, 820, 740 cm⁻¹

NMR (DMSO-d₆, δ) : 1.40-1.70 (4H, m), 2.42 (4H, t, J=5Hz), 2.60 (2H, t,J=5Hz), 2.93 (3H, s), 3.06 (2H, d, J=5Hz), 3.92 (2H, t, J=5Hz), 6.14(1H), s), 7.05-7.53 (7H, m), 7.78 (1H, s)

What we claim is:
 1. A compound of the formula: ##STR5## in which R¹ andR² are each hydrogen, halogen, nitro, amino, ureido, N'-(lower)alkylureido, lower alkylsulfonylamino, protected amino, hydroxyamino,lower alkyl, hydroxy, protected hydroxy, sulfamoyl, carboxy, protectedcarboxy, mercapto, lower alkylthio, hydroxy(lower) alkyl or protectedhydroxy(lower) alkyl, morpholinocarbonyl or morpholino(lower) alkyl;R³is aryl which may have suitable substituent(s), and A is lower alkylene,or pharmaceutically acceptable salts thereof.
 2. A compound according toclaim 1, wherein said protected carboxy group is selected from the groupconsisting of carbamoyl and lower alkoxycarbonyl, said protected aminogroup is selected from the group consisting of lower alkanoyl,trihalo(lower)alkanoyl, lower alkoxycarbonyl, carbamoyl,N-(lower)alkylcarbamoyl and lower alkylsulfonyl, said protected hydroxygroup is selected from the group consisting of lower alkyl, acyl, andar(lower)alkyl, and wherein said protected hydroxy(lower)alkyl isselected from the group consisting of lower alkoxy(lower)alkyl andtriphenyl(lower)alkoxy(lower)alkyl.
 3. The compound of claim 1,whereinR¹ and R² are each hydrogen, halogen, nitro, amino, ureido,N'-(lower)-alkylureido, lower alkylsulfonylamino, acylamino,hydoxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy,esterified carboxy, carbamoyl, mercapto, morpholinocarbonyl,morpholino(lower)alkyl, lower alkylthio, hydroxy(lower)alkyl, loweralkoxy(lower)alkyl or triphenyl(lower)alkoxy(lower)alkyl, and R³ isphenyl which is unsubstituted or substituted by a group consisting ofhalogen and lower alkyl.
 4. The compound of claim 3, whereinR¹ and R²are each hydrogen, halogen, nitro, amino, lower alkanoylamino,hydroxyamino, trihalo(lower)alkanoylamino, lower alkoxycarbonylamino,ureido, N'-(lower)alkylureido, lower alkylsulfonylamino, lower alkoxy,lower alkyl, hydroxy, sulfamoyl, carboxy, lower alkoxycarbonyl,carbamoyl, mercapto, morpholinocarbonyl, morpholino(lower)alkyl, loweralkylthio, hydroxy(lower)alkyl or protected hydroxy(lower)alkyl, and R³is phenyl which is unsubstituted or substituted by a group consisting ofhalogen and lower alkyl.
 5. The compound of claim 4, whereinR¹ and R²are each hydrogen, halogen, nitro, amino, C₁ -C₄ alkanoylamino,trihalo(C₁ -C₄)alkanoylamino, hydroxyamino, C₁ -C₄ -alkoxycarbonylamino,ureido, N'-(C₁ -C₄)-alkylureido, C₁ -C₄ alkylsulfonylamino, C₁ -C₄alkoxy, C₁ -C₄ alkyl, hydroxy, sulfamoyl, carboxy, C₁ -C₄alkoxycarbonyl, carbamoyl, mercapto, morpholinocarbonyl, morpholino(C₁-C₄)alkyl, C₁ -C₄ alkylthio, hydroxy(C₁ -C₄)alkyl, C₁ -C₄ alkoxy(C₁-C₄)alkyl or triphenyl(C₁ -C₄)alkoxy(C₁ -C₄)alkyl, R³ is phenyl which isunsubstituted or substituted by a group consisting of halogen and C₁ -C₄alkyl, and A is C₁ -C₆ alkylene.
 6. The compound of claim 5, whereinR¹and R² are each hydrogen, halogen, nitro, amino, acetamido,trifluoroacetamido, ethoxycarbonylamino, ureido, N'-ethylureido,methylsulfonylamino, ethylsulfonylamino, methoxy, hydroxy, sulfamoyl,carboxy, hydroxyamino, carbamoyl, morpholinocarbonyl, morpholinomethyl,hydroxymethyl, methoxymethyl or trityloxymethyl, R³ is phenyl, 4-tolylor 4-fluorophenyl, and A is tetramethylene.
 7. A compound according toclaim 1, in which R¹ and R² are each hydrogen, halogen, nitro, amino,ureido, N'-(lower)alkylureido, lower alkylsulfonylamino, hydoxyamino,lower alkoxy, hydroxy, sulfamoyl, carboxy, mercapto, lower alkylthio,hydroxy(lower)alkyl, morpholinocarbonyl or morpholino(lower)alkyl; andR³is aryl which may be substituted by one or more substitutents selectedfrom the group consisting of fluorine, chlorine, bromine, iodine andlower alkyl.
 8. A compound of claim 6, which is selected from the groupconsisting of3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6-methylsulfonylamino-1,2,3,4-tetrahydroquinazoline-2,4-dioneand7-hydroxyamino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione.9. A compound of the formula: ##STR6## in which R¹ is hydrogen,R² islower alkylsulfonylamino R³ is phenyl, and A is lower alkylene, orpharmaceutically acceptable salts thereof.
 10. A compound, which is6-ethylsulfonylamino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dioneor its acid addition salt.
 11. A compound according to claim 1, which is6-Chloro-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione.12. A dopamine receptor agonist, 5-HT receptor antagonist and α₁-receptor antagonist pharmaceutical composition comprising, as an activeingredient, an effective amount of a compound of claim 1 in admixturewith a pharmaceutically acceptable carrier or excipient.
 13. A methodfor the treatment of dopamine receptor mediated diseases, 5-HT receptormediated diseases or α₁ receptor mediated diseases which comprisesadministering an effective amount of a compound of claim 12 to a humanbeing or animal.